tbuckley/cabot-search huggingface dataset:
Real-world impact of olaparib use in patients (pts) with advanced pancreatic cancer (PC) harboring germline <i>BRCA</i>1/2 (g<i>BRCA</i>) mutations.
Authors: Michele Milella, Giulia Orsi, Mariacristina Di Marco, Lisa Salvatore, Letizia Procaccio, Silvia Noventa, Silvia Bozzarelli, Ingrid Garajova, Enrico Vasile, Guido Giordano, Marina Macchini, Alessandro Cavaliere, Marina Gaule, Giulia Barsotti, Andrea Palloni, Giampaolo Tortora, Isabella Sperduti, Michele Reni
Journal: Journal of Clinical Oncology (2023)

e16278 Background: g BRCA mutations are found in approximately 8% of Italian PC pts screened within 3 months from diagnosis. g BRCA PC pts display enhanced sensitivity to platinum-based chemotherapy (CHT) and PARP inhibitors, such as olaparib. In metastatic g BRCA PC pts, maintenance olaparib after platinum-based CHT doubled PFS and resulted in twice as many long-term (3-yr) survivors (34% versus 18%) in the randomized POLO trial. However, despite guideline recommendations, olaparib is currently not reimbursed in Italy in metastatic g BRCA PC pts, based on the absence of significant differences in median OS. Methods: We analyzed the impact of exposure to olaparib on OS from the start of I-line treatment in a cohort of 114 Italian g BRCA PC pts, whose clinical characteristics and outcomes in response to first () and subsequent chemotherapy lines have been previously reported ( 10.1016/j.esmoop.2021.100238 ; 10.1038/s41416-022-02086-w ). Results: Clinical characteristics of patients who did or did not receive olaparib were well balanced, except for baseline CA19.9 levels (significantly lower in patients who received olaparib, p=0.043) and exposure to platinum-containing chemotherapy (significantly less in patients who did not receive olaparib, p&lt;0.0001). In the entire cohort of g BRCA PC pts, OS from the start of I-line treatment for metastatic disease was significantly (p=0.02) longer in pts who had been exposed to olaparib in any treatment line (n=53). Since previous surgery and response to I-line chemotherapy were strong independent predictors of OS at multivariate analysis, we analyzed pts who were diagnosed with stage IV (M+, n=87) disease and pts who did not experience PD as best response to I-line chemotherapy (no PD, n=94), separately. A statistically significant difference in OS favoring g BRCA PC pts who were exposed to olaparib in any line of treatment was observed in the M+ cohort (p=0.0025), in the no PD cohort (p=0.049), but not in the M+/no PD cohort (n=73, p=0.057) or in the POLO-like population (I-line maintenance; n=60, p=0.334). Conclusions: In g BRCA PC pts, exposure to olaparib in any line of treatment in a real-world setting significantly impacts on OS; timing and setting of administration remain to be determined in order to optimize survival advantage. [Table: see text]
LITESPARK-024: Randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma (RCC).
Authors: David F. McDermott, Avivit Peer, Neeraj Agarwal, Michael B. Atkins, Jerry Cornell, Rodolfo F. Perini, Kenneth F. Grossmann, Howard Gurney
Journal: Journal of Clinical Oncology (2023)

TPS4603 Background: Immunotherapy is a standard-of-care first-line treatment for advanced clear cell RCC (ccRCC). However, many patients (pts) will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of ccRCC cases and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated pts with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in pts with advanced ccRCC. In both parts, pts with measurable disease per RECIST v1.1, a KPS score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component with disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, and PFS per RECIST v1.1 by investigator assessment, OS, and safety and tolerability. Enrollment began in July 2022. Clinical trial information: NCT05468697 .
The relationship between the change with neoadjuvant chemotherapy in the tumor-infiltrating lymphocyte (TIL) expressions and pathological response in breast cancer patients.
Authors: Ahmet Bilici, Sabin Goktas Aydin, Asli Cakir, Omer Fatih Olmez, Vedat Bugra Erol
Journal: Journal of Clinical Oncology (2023)

3114 Background: Many prognostic biomarkers for survival have been studied in the neoadjuvant setting for locally advanced breast cancer (LABC). Our study assessed the correlation between the change in tumour-infiltrating lymphocytes (TIL) before and after neoadjuvant chemotherapy (NAC) in breast tissue and its impact on survival in patients with LABC. Methods: Eighty-four LACB patients were retrospectively analysed in this study. TIL was assessed by means of immunohystochemistry (Eclipse Ni, Nikon, Japan) in paraffin-embedded blocks obtained by core-needle biopsy or surgical specimen with respect to the 'TIL working group' criteria. Results: TIL scores were grouped as 0%, &lt;10%, 10-50%, and &gt;50%, the median TIL percentage was 17.5% before NAC and 5% after NAC, and the difference was statistically significant (p&lt;0.001). Postop-Ki-67 (p=0.005), molecular subtype (p=0.027), pre-NAC TIL score (p=0.006), post-NAC TIL score (p&lt;0.001), postop-Ki-67 (p=0.005) and preoperative residual cancer burden tumour-infiltrating lymphocyte (RCB-TIL) (p&lt;0.001) were significantly correlated with pCR. Higher TIL scores were significantly associated with higher PCR rates. Univariate analysis for disease-free survival (DFS) and overall survival (OS) revealed that postop-Ki-67 level and presence of pCR and postoperative ki-67 score (p=0.031) were significant prognostic factors, respectively. The independent prognostic factor for DFS were postop-Ki-67 score (p=0.012, RR: 6.16, 95% CI: 1.48-9.12), post-NAC TIL score (p=0.041, RR: 0.42, 95% CI: 0.16-1.06) and the presence of pCR (p=0.038, RR: 0.10, 95% CI: 0.01-0.87). Logistic regression analysis showed that a preoperative ki-67 score greater than 14% (p=0.001, OR: 4.55; 95% CI: 0.11-1.49), a postoperative ki-67 score equal to or lower than 14% (p=0.011, OR: 1.10; 95% CI: 0.42-2.29), preop-grade 3 (p=0.01, OR: 2.65; 95% CI: 0.85-3.14), low postop-TIL score (p&lt;0.001, OR: 3.14; 95% CI: 0.79-4.11) were significant predictive factors for pCR. Conclusions: Our study confirms the hypothesis that TIL expressions may be therapeutic targets, especially in specific molecular breast cancer subtypes.
Early detection of lung cancer using small RNAs.
Authors: Amita Sharma, Tobias Sikosek, Rastislav Horos, Timothy Rajakumar, Kaja Tikk, Christian Schumann, Stephan Walterspacher, Petros Christopoulos, Martin H. Schuler, Kaid Darwiche, Christian Taube, Balazs Hegedus, Klaus Rabe, Kimberly M. Rieger-Christ, Francine Jacobnson, Clemens Aigner, Alexander A. Bankier, Martin Reck, Bruno Steinkraus
Journal: Journal of Clinical Oncology (2023)

3035 Background: Low-dose computed tomography (LDCT) screening can significantly reduce lung cancer mortality. However, annual screening is limited by low adherence in the USA and still not broadly implemented in Europe. As a result, &lt;10% of lung cancers are detected through existing programs. Thus, there is great need for additional diagnostic modalities, such as a blood test that could be deployed in the primary care setting. Methods: We prospectively recruited 1,189 patients meeting the 2013 USPSTF screening criteria for lung cancer and collected stabilized whole blood. Ultra-deep small RNA sequencing was performed with a method to remove highly abundant erythroid RNAs, opening bandwidth for the detection of less abundant species originating from plasma or the immune cellular compartment. We utilized 100 random data splits to train and evaluate logistic regression classifiers using small RNA expression, discovered an 18-small RNA feature consensus signature (miLung), and validated this in an independent cohort (246 patients). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. Results: We generated diagnostic models and report a median ROC AUC of 0.86 (95% CI 0.84-0.86) in the discovery cohort, and generalized performance of 0.84 in the validation cohort. Diagnostic performance increased stage-dependently from 0.73 (95% CI 0.71-0.76) for Stage I to 0.90 (95% CI 0.89-0.90) for Stage IV. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased following surgery with curative intent. In additional experiments, dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted via home-sampling. Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to LDCT screening for early detection of smoking-associated lung cancer. Clinical trial information: NCT03452514 . [Table: see text]
Comprehensive clinical tumor RNA sequencing for children with cancer.
Authors: Olena Morozova Vaske, Anouk van den Bout, Molly McCabe, Kathryn Echandia-Monroe, Holly Beale, Ellen T. Kephart, Katrina Learned, Jolene Draper, Geoff Lyle, Isabel Bjork, Patrick Devine
Journal: Journal of Clinical Oncology (2023)

e15067 Background: Cancer is the number one cause of death by disease for children in the United States. The underlying cause for most childhood cancers is unknown and unlike most adult cancers, childhood cancers harbor fewer coding mutations compared to adult cancers and are often driven by epigenetic deregulation. The functional impact of both genetic and epigenetic abnormalities can be detected from the analysis of tumor RNA. While tumor RNA profiling has entered several clinical trials, it is not utilized comprehensively and there is limited availability of clinical-grade RNA-Seq assays. We have published preliminary evidence of the utility of using research tumor RNA information in the pediatric oncology clinic. The next step is to develop an RNA-Seq assay that identifies gene fusions, expressed mutations, and important gene expression abnormalities in pediatric tumors. Methods: To validate our RNA-Seq assay pipeline, we have started with fusion detection and compared our results with a CLIA-validated DNA-based assay. We used RNA-Seq data generated from three fusion-positive cell lines to define the minimum of Mapped, Exonic, Non-Duplicate (MEND) reads necessary to accurately identify known fusions. Results: We found that the fusion, which has moderate expression (above 3 log2(TPM+1)), was consistently detectable in subsets containing at least 1 million MEND reads (Table). We next evaluated the precision of this finding. The fusion was detected in each of 21 additional subsets of 2 million MEND reads with replacement, but in only 71% of 21 subsets of 1 million MEND reads. In RNA-Seq data generated from tumor samples preserved with FFPE, we compared our RNA-based fusion findings with structural variants detected with the DNA-based gene panel test UCSF 500. Seven positive results were concordant, and one negative result was concordant. Two negative findings were positive by UCSF 500. Evaluation of these discordant results is ongoing, but the expression data indicates that the RNA result for one, a TMPRSS-ERG fusion, is accurate. To incorporate gene expression into our assay, we assessed the precision of gene expression measurements. In a preliminary dataset of three technical replicates, we found that the 95% confidence interval of expression values greater than 3 log2(TPM+1) is 4.5% of the measured value. Comprehensive clinical validation of our protocol will involve additional previously-characterized cancer samples. Conclusions: In summary, these data establish and validate key analytical parameters necessary for successful implementation of RNA-Seq analysis in the pediatric oncology clinic and advance our ultimate goal of bringing the most innovative molecular diagnostic methods to every child with cancer. [Table: see text]
Atezolizumab and bevacizumab in advanced hepatocellular carcinoma: Real-world data.
Authors: Nomi Bezalel, Yana Davidov, Mariya Likhter, Oranit Cohen Ezra, Yael Inbar, Naama Halpern, Ben Boursi, Tamar Beller, Ron Pery, Einat S Shmueli, Ido Nachmany, Ziv Ben Ari, Ofer Margalit
Journal: Journal of Clinical Oncology (2023)

e16167 Background: Treatment of advanced unresectable hepatocellular carcinoma (HCC) has advanced substantially in the past few years with the use of immunotherapy. The IMbrave 150 phase III study assessed the combined treatment of atezolizumab plus bevacizumab (atezobev) and has demonstrated better overall and progression-free survival compared with sorafenib. We aimed to assess the efficacy and toxicity of atezobev in real-world data. Methods: We reviewed the medical records of patients with a diagnosis of advanced HCC treated at the Sheba Medical Center between January 2020 and February 2023. Eligible patients were those treated with atezobev as first line systemic therapy. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment was performed according to the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: We identified 37 patients that were treated with atezobev, mean age of the study population was 70 (IQR 60-72), 19% were females (n = 7), median ECOG performance status was 1 (IQR 0-1.5) and HCC etiology was non-viral in 35% (n = 13) and viral (HBV/HCV) in 65% of patients (n = 24). Overall response rate (ORR) was 29.7% (n = 11), stable disease was noted in 27.0% (n = 10) and progressive disease in 43.2% (n = 16) of patients. In comparison, the ORR reported in the IMbrave 150 study was 27%. There was no difference in response rate according to previous local treatment or HCC etiology. Grade 3/4 adverse events included grade 3 hepatitis (10.8%, n = 4), grade 3 diarrhea (2.7%, n = 1), and grade 4 infusion-related reaction (2.7%, n = 1). In comparison, the IMbrave 150 study reported grade 3/4 hepatitis, diarrhea, and infusion-related reaction in 7.0%, 1.8% and 2.4% of patients, respectively. Conclusions: In this cohort of advanced HCC patients treated in a large tertiary medical center, the efficacy and toxicity profile of atezobev was similar to that reported in the IMbrave 150 phase III study.
Artificial intelligence model for predicting the efficacy of sintilimab plus chemotherapy in treating patients with esophageal squamous cell carcinoma.
Authors: Kefeng Wang, Duoguang Wu, Wenjian Wang, Kai Lei, Ruihao Liang, Binghua Tan, Xueting Hu, Lin Li, Yingcheng Lyu, Zhizheng Wang, Yanwu Zeng, Fei Pang, Kai Wang, Huayue Lin, Minghui Wang
Journal: Journal of Clinical Oncology (2023)

e16030 Background: Blockade of programmed cell death 1 (PD-1) could induce tumor regression in patients with advanced esophageal squamous cell carcinoma (ESCC), although little is known about the biomarker to guide immunochemotherapy. In this study, we sought to evaluate the efficacy and discover biomarkers and establish an artificial intelligence (AI) model to predict the efficacy of the combination of sintilimab and chemotherapy in the treatment of patients with ESCC. Methods: Fifty-nine (59) patients enrolled in our study received chemotherapy with sintilimab and follow-up data were available. Treatment outcomes were assessed using the Response Evaluation Criteria in Solid Tumors (v1.1). Eleven (11) clinicopathologic characteristics including age, albumin, HLA-1 evolutionary divergence (HED), TMB, body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelets, hemoglobin, stage, sex, leukocyte, lymphocyte and therapy were collected. Results: Thirty-four (34) patients with ESCC who received sintilimab as first-line chemotherapy had a median follow-up of 13.7 (range, 0.53-35.57) months. At the time of analysis, six (6, 17.6%) patients were still receiving treatment, 24 patients achieved PR, and the confirmed ORR was 67.65%. Four (4) patients had SD and the DCR was 79.41%. Median PFS (mPFS) was 10.06 months. Median overall survival (mOS) was 23.27 months. The mPFS of the PD-L1 positive population was significantly better than that of the PD-L1 negative population (19.23 months vs. 6.57 months, p = 0.046). There was no significant difference in mPFS and mOS between the high and low TMB groups. Patients were divided into response (CR or PR) and non-response (SD or PD) groups according to their response to combined immunotherapy. The response rate of patients with wild-type MET was higher than that of patients with MET mutation (75% vs. 25%, p=0.0889). Compared to patients with wild-type BRCA2, patients with mutant BRCA2 had a significantly shorter mPFS (4.2 months vs. 13.3 months, p=0.027). Based on the efficacy data and 11 additional clinicopathologic characteristics of the 59 patients who received sintilimab in combination with chemotherapy, a random forest AI model was constructed to predict response to immunochemotherapy. Patients were randomly divided into a training set and a test set in a 6:4 ratio. In the test set, the top three predictive biomarkers were HED, age, and BMI. The area under the curve of the predictive model in the test set was 0.82. Conclusions: Sintilimab combined with chemotherapy could be an effective treatment for advanced ESCC, and an AI model based on multiple clinical features at baseline could predict the efficacy of immunochemotherapy. Further studies with larger sample size are needed to validate our findings.
Heterofunctional polymeric degrading chimeras (HYDRAC) for targeted protein degradation.
Authors: Max Mu Wang, Mihai Ioan Truica, Brayley Gattis, Sarki Abdulkadir, Nathan Gianneschi
Journal: Journal of Clinical Oncology (2023)

e15106 Background: Here we utilize a novel proteomimetic polymer platform technology which packages peptide side chains as globular structures with benificial emergent properties for the development of compounds capable of targeted protein degradation. We refer to this class of compounds as Heterofunctional polYmeric DegRAding Chimeras (HYDRACs) and demonstrate the selective degradation of the oncoprotein Myc as a proof-of-concept. Methods: HYDRACs were generated using ring-opening metathesis polymerization (ROMP), resulting in structures highly resistant to proteolysis. Heterofunctional constructs were designed incorporating secondary sequences in addition to Myc-targeting H1. The degron sequence (RRRG) was incorporated to engage endogenous cellular machinery for targeted protein degradation. Immunofluorescence/confocal microscopy were used to assess cellular penetration; cellular viability assays coupled with use of both cellular (isogenic pairs, Myc-dependent and independent lines) and biochemical (scrambled H1 sequence, homopolymers, monomeric peptides) controls were used to assess tumor antiproliferative effects and Myc-specific responses. Myc target engagement was assessed via immunoprecipitation assays, NMR, circular dichroism, and fluorescence polarization with protein degradation monitored by Western blot. A CRISPR knockdown library screen of all known E3 ligases and mass spec was used to identify pathways responsible for HYDRAC-induced protein degradation. Results: A library of HYDRACs with narrow polydispersity and predetermined degrees of polymerization were generated. These compounds are cell-penetrating with antiproliferative effects at micromolar IC50s. HYDRAC treatment resulted in significant decreases in Myc protein levels, which was rescued by inhibition with MG132 and MLN4924. RNAseq showed selective overexpression of Myc pathway genes. Biophysical analysis showed strong HYDRAC-Myc interactions, supported by the presence of Myc protein following pull-down of biotin-terminated HYDRACs. Identification of E3 ligases implicated in the degradation pathway using a combination of a CRISPR knock down library and mass spectrometry are ongoing. Mice bearing Myc-CaP tumors showed delayed tumor growth following treatment with Myc-degrading HYDRACs. Studies on biodistribution and pharmacokinetic profile of the compound, as well as the ability to degrade other proteins of interest using combinations of degron sequences are ongoing. Conclusions: The presented work demonstrates the feasibility of HYDRACs for targeted protein degradation of Myc, providing rationale for further studies in Myc-driven tumor models. This successful demonstration of this first-in-class compound also opens the door for the development of HYDRACs targeting other proteins of interest and incorporation of different E3 ligase recruiters for tissue or disease-specific activity.